Mechanisms of differential desensitization of metabotropic glutamate receptors

SUMMARY

G protein-coupled receptors (GPCRs) interact with intracellular transducers to control both signal initiation and desensitization, but the distinct mechanisms that control the regulation of different GPCR subtypes are unclear. Here we use fluorescence imaging and electrophysiology to examine the metabotropic glutamate receptor (mGluR) family. We find distinct properties across subtypes in both rapid desensitization and internalization, with striking differences between the group II mGluRs. mGluR3, but not mGluR2, undergoes glutamate-dependent rapid desensitization, internalization, trafficking, and recycling. We map differences between mGluRs to variable Ser/Thr-rich sequences in the C-terminal domain (CTD) that control interaction with both GPCR kinases and β-arrestins. Finally, we identify a cancer-associated mutation, G848E, within the mGluR3 CTD that enhances β-arrestin coupling and internalization, enabling an analysis of mGluR3 β-arrestin-coupling properties and revealing biased variants. Together, this work provides a framework for understanding the distinct regulation and functional roles of mGluR subtypes.

Graphical abstract

In brief

Abreu et al. use high-resolution imaging and electrophysiology to reveal distinct desensitization properties across subtypes of the metabotropic glutamate receptor (mGluR) family. Comparative analysis of group II mGluR subtypes identifies a Ser/Thr-rich region in the C-terminal domain of mGluR3 that mediates both rapid GRK-mediated desensitization and arrestin-mediated internalization.